Poxviruses form a group of large, double-stranded DNA viruses that have adapted to replicate in numerous hosts. One adaptive mechanism that many poxviruses have utilized is the acquisition of host genes that allow the viruses to evade the host's immune system and/or facilitate viral replication (Bugert and Darai, Virus Genes 21:111, 2000; Alcami et al., Semin. Virol. 8:419, 1998; McFadden and Barry, Semin. Virol. 8:429, 1998). This process has been facilitated by the relatively large size and complexity of the poxvirus genome; vaccinia virus, a prototype poxvirus widely used as a smallpox vaccine, has a genome of approximately 190 Kbp that could potentially encode more than 200 proteins (Goebel et al., Virology 179:247, 1990). Despite the fact that the entire genome of vaccinia virus has been sequenced, the function of many of the potential open reading frames (ORFs), and the existence of polypeptides encoded thereby, remains unknown.
A41L is an ORF present in several different poxviruses, including Cowpox virus (CPV), vaccinia virus (strains Copenhagen, Ankara, Tian Tan and WR) and variola virus (including strains Harvey, India-1967 and Garcia-1966). An ORF from vaccinia strain WR referred to as SalF4L in Howard et al., Virology 180:633, 1991, was noted to exhibit week similarity with an ORF from Shope fibroma virus (SFV) referred to therein as T1. The protein encoded by the SFV T1 ORF is referred to as p35 in Martinez-Pomarres et al. (Virology 206:591, 1995), who state that SaTF4L did not exhibit significant homology with p35, p35 binds to, and inhibits the activity of, certain chemokines (Smith et al., Virology 236:316, 1997; U.S. Pat. No. 5,871,740). An A41L protein made by recombinant baculovirus expression was reported to specifically bind the chemokines Mig and IP-10, but not other chemokines, by Smith et al. in WO98/37217.
The leukocyte common-antigen-related protein (LAR) is a prototypic member of the superfamily of receptor-like protein tyrosine phosphatases (PTPs) with immunoglobulin and fibronection type III-like motifs in the extracellular domain (Streuli et al., J. Exp. Med. 168:1523, 1988). Several alternatively spliced variants of LAR have been identified, and are believed to be developmentally regulated (O'Grady et al., J. Biol. Chem. 269:25193, 1994; Zhang and Longo, J. Cell. Biol. 128:415, 1995; Honkaniemi et al., Mol. Brain. Res. 61:1, 1998). In humans, the LAR gene maps to chromosome 1p32, a region that is frequently deleted in tumors of neuroectodermal origin (Jirik et al., Cytogenet. Cell Genet. 61:266, 1992).
Changes in LAR expression and splicing have been associated with changes in the ability of cells to proliferate (Yang et al., Carcinogenesis 21:125; Tisi et al., J. Neurobiol. 42:477, 2000). Transfection of a human breast carcinoma cell line that overexpresses the protein tyrosine kinase p185neu with cDNA for LAR resulted in suppression of tumor cell growth (Zhai et al., Mol. Carcinogen. 14:103, 1995), suggesting a role for LAR as a tumor suppressor. The related PTP, CD45, suppresses Janus kinase (JAK) kinases and negatively regulates cytokine receptor signaling; LAR also dephosphorylates JAK2 (Irie-Sasaki et al., Nature 409:349, 2001). LAR has also been found to associate with the insulin receptor, and play a role in glucose homeostasis (Ahmad and Goldstein, J. Biol. Chem. 272:448, 1997; Ren et al., Diabetes 47:493, 1998). These and other functional roles of LAR are discussed in EP 1 092 772 (Yamamoto et al.; 2001).
Heretofore, the function of any peptide encoded by an A41L ORF was unclear. Moreover, despite a role being known for LAR in glucose metabolism and/or cell replication, it was previously unknown whether LAR plays a role in an immune or inflammatory response, or what such role might be. Accordingly, there is a need in the art to determine the biologic function(s) of a protein or proteins encoded by an A41L ORF, and to determine the role of LAR in an immune or inflammatory response.